The metabolism of exogenous nutrients administered is markedly altered by infection. One of the hallmarks of an individual that develops an infection while receiving nutritional support is hyperglycemia. There is also a concomitant increase in the metabolic rate and the inability of exogenous nutrients to suppress the elevated nitrogen excretion, fat oxidation and increased gluconeogenesis. The primary cause of the hyperglycemia is due to the inability of the body to efficiently dispose of the exogenous glucose. The role of specific tissues in contributing to the impairment is unclear. Based upon our studies the liver is a major site of glucose disposal (approximately 50 percent of the exogenous glucose infused) in normal animals receiving total parenteral nutrition and the uptake of glucose by the liver is markedly suppressed by infection. And peripheral tissues dispose of the glucose carbon. It is also known that the route of nutrient support (enteral or parenteral) alters the ability of the liver to take up glucose in the acute setting but this benefit does not persist chronically. The first goal of the proposal is to determine the time course of and the mechanism for the normal adaptation to nutritional support given enterally and parenterally. The second goal is to determine if the route by which glucose is delivered can chronically regulate liver glucose uptake and if it is affected by infection. The third goal to determine how chronic hyperinsulinemia, hyperglucagonemia and hyperglycemia interact to regulate liver glucose uptake during infection. Experiments will be carried out in chronically catheterized conscious dogs receiving continuous nutritional support. Hepatic glucose metabolism (unidirectional hepatic glucose uptake and production, glucose oxidation) will be assessed using a combination of tracer and arterio-venous difference techniques. In addition we will simultaneously assess limb glucose uptake and disposal. While previous work has been examining the response of whole body glucose metabolism to infection, we will be uniquely able to directly examine the role that individual organs (liver muscle) plays in the infection induced modulation of nutrient disposition. And by using Pharmacological techniques (somatostatin, phosphorylase a inhibition) we can not only determine the factors responsible for the impairment but we will be able to determine their mechanism as well.